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ID PMID Title PublicationDate abstract
20597111 Effect of interactions of glutathione S-transferase T1, M1, and P1 and HMOX1 gene promoter 2010 Nov OBJECTIVE: Glutathione S-transferase (GST) genes as well as heme oxygenase 1 gene (HMOX1) encode enzymes that detoxify carcinogens and protect against oxidative stress. This study was undertaken to examine the impact of gene-smoking interactions on susceptibility to rheumatoid arthritis (RA). METHODS: Caucasian patients with RA and matched control subjects (n = 549 each) were selected from the Nurses' Health Study. Genotyping of the patients' blood by TaqMan and BioTrove assays identified homozygous deletions at the M1 and T1 loci of GST (GSTM1-null and GSTT1-null, respectively) as well as alleles for GSTP1 (rs1695) and HMOX1 (rs2071746). In addition, the effect of gene-smoking interactions on the risk of all RA and RA serologic phenotypes was studied in separate logistic models that were adjusted for covariates. Multiplicative interactions were assessed by including a product term in a logistic model, and additive interactions were assessed using the attributable proportion (AP) due to interaction. For replication of the results, analyses revealing significant interactions were repeated in an independent case-control cohort from the Epidemiological Investigation of Rheumatoid Arthritis study. RESULTS: For the risk of all RA, multiplicative (P = 0.05) and additive (AP = 0.53, P = 0.0005) interactions between the GSTT1-null polymorphism and smoking and multiplicative interactions (P = 0.05) between HMOX1 and smoking were observed. For the risk of seropositive RA, multiplicative (P = 0.01) and additive (AP = 0.62, P < 0.0001) interactions between GSTT1-null and smoking and additive interactions (AP = 0.41, P = 0.03) between HMOX1 and smoking were observed. After correction for multiple comparisons, the additive interactions between GSTT1-null and smoking remained significant. The M1-null and P1 variants of GST did not show significant interactions, and no associations with seronegative RA were observed. In replication analyses, significant multiplicative interactions (P = 0.04) and additive interactions (AP = 0.32, P = 0.02) were observed between GSTT1-null and smoking in the risk of anti-citrullinated protein antibody-positive RA. CONCLUSION: Significant gene-environment interactions between the GSTT1-null polymorphism and heavy smoking were observed when assessing the risk of RA. Future studies are needed to assess the impact of these interactions on RA prediction.
19625101 Regulation of macrophage function by sphingosine-1-phosphate. 2009 The bioactive lipid sphingosine-1-phosphate (S1P) fulfils manifold tasks in the immune system acting in auto- and/or paracrine fashion. This includes regulation of apoptosis, migration and proliferation. Upon its generation by sphingosine kinases from plasma membrane sphingolipids, S1P can either act as a second messenger within cells or can be released from cells to occupy a family of specific G-protein-coupled receptors (S1P1-5). This diversity is reflected by the impact of S1P on macrophage biology and function. Over the last years it became apparent that the sphingosine kinase/S1P/S1P-receptor signalling axis in macrophages might play a central role in the pathogenesis of inflammatory diseases such as atherosclerosis, asthma, rheumatoid arthritis and cancer. Here, we summarize the current knowledge of the function of S1P in macrophage biology and discuss potential implications for pathology.
21138984 A systemic lupus erythematosus gene expression array in disease diagnosis and classificati 2011 Mar Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level, multiple factors using diverse biochemical and molecular pathways have been recognized. Succinct recognition and classification of clinical disease subsets, as well as the availability of disease biomarkers, remains largely unsolved. Based on information produced by the present authors' and other laboratories, a lupus gene expression array consisting of 30 genes, previously claimed to contribute to aberrant function of T cells, was developed. An additional eight genes were included as controls. Peripheral blood was obtained from 10 patients (19 samples) with SLE and six patients with rheumatoid arthritis (RA) as well as 19 healthy controls. T cell mRNA was subjected to reverse transcription and PCR, and the gene expression levels were measured. Conventional statistical analysis was performed along with principal component analysis (PCA) to capture the contribution of all genes to disease diagnosis and clinical parameters. The lupus gene expression array faithfully informed on the expression levels of genes. The recorded changes in expression reflect those reported in the literature by using a relatively small (5 ml) amount of peripheral blood. PCA of gene expression levels placed SLE samples apart from normal and RA samples regardless of disease activity. Individual principal components tended to define specific disease manifestations such as arthritis and proteinuria. Thus, a lupus gene expression array based on genes previously claimed to contribute to immune pathogenesis of SLE may define the disease, and principal components of the expression of 30 genes may define patients with specific disease manifestations.
20223142 [Secondary amyloidosis of the bladder and massive hematuria]. 2010 Jan OBJECTIVE: To report four additional cases of secondary amyloidosis of the bladder, an extremely rare condition, as shown by the cases reported in the literature. MATERIALS AND METHODS: Four clinical cases are reported, all of them occurring as hematuria, which was massive and fulminant and resulted in death in three patients. RESULTS: Secondary amyloidosis of the bladder is of the AA type, which is more common in females and mainly secondary to rheumatoid arthritis, but also to ankylosing spondylitis and long-standing chronic inflammatory conditions. Hematuria is the main and virtually only symptom. A pathological and immunohistochemical study confirmed diagnosis. All three patients who experienced massive, fatal hematuria had an intercurrent condition requiring urethral catheterization, which was the triggering factor. CONCLUSIONS: Despite its rarity, as shown by the few cases reported, secondary amyloidosis of the bladder should be considered in patients already diagnosed with systemic amyloidosis and/or the conditions reported who require simple urethral catheterization.
21198194 Computer-aided interpretation approach for optical tomographic images. 2010 Nov A computer-aided interpretation approach is proposed to detect rheumatic arthritis (RA) in human finger joints using optical tomographic images. The image interpretation method employs a classification algorithm that makes use of a so-called self-organizing mapping scheme to classify fingers as either affected or unaffected by RA. Unlike in previous studies, this allows for combining multiple image features, such as minimum and maximum values of the absorption coefficient for identifying affected and not affected joints. Classification performances obtained by the proposed method were evaluated in terms of sensitivity, specificity, Youden index, and mutual information. Different methods (i.e., clinical diagnostics, ultrasound imaging, magnet resonance imaging, and inspection of optical tomographic images), were used to produce ground truth benchmarks to determine the performance of image interpretations. Using data from 100 finger joints, findings suggest that some parameter combinations lead to higher sensitivities, while others to higher specificities when compared to single parameter classifications employed in previous studies. Maximum performances are reached when combining the minimum/maximum ratio of the absorption coefficient and image variance. In this case, sensitivities and specificities over 0.9 can be achieved. These values are much higher than values obtained when only single parameter classifications were used, where sensitivities and specificities remained well below 0.8.
20404044 Evidence for the hypothesis that 10-formyldihydrofolate is the in vivo substrate for amino 2010 Mar We postulate that 10-formyl-7,8-dihydrofolate (10-HCO-H(2)folate), not 10-formyl-5,6,7,8-tetrahydrofolate (10-HCO-H(4)folate), is the predominant in vivo substrate for mammalian aminoimidazolecarboxamide ribotide (AICAR) transformylase, an enzyme in purine nucleotide biosynthesis de novo, which introduces carbon 2 (C(2)) into the purine ring. 10-HCO-H(2)folate exists in vivo as labeled 10-formyl-folic acid (10-HCO-folic acid: an oxidation product of 10-HCO-H(4)folate and 10-HCO-H(2)folate) and is found after doses of labeled folic acid in humans or laboratory animals. The bioactivity of the unnatural isomer, [6R]-5-formyltetrahydrofolate, in humans is explained by its in vivo conversion to 10-HCO-H(2)folate. The structure and active site of AICAR transformylase are not consistent with other enzymes that utilize 10-HCO-H(4)folate. Because 10-HCO-H(4)folate is rapidly oxidized in vitro to 10-HCO-H(2)folate by cytochrome C alone and in mitochondria, it is hypothesized that this process takes place in vivo. In vitro data indicate that 10-HCO-H(2)folate is kinetically preferred over 10-HCO-H(4)folate by AICAR transformylase and that this enzyme may not have access to sufficient supplies of 10-HCO-H(4)folate. Methotrexate blockage of the AICAR transformylase process in patients with rheumatoid arthritis suggests that dihydrofolate (H(2)folate) reductase is involved and is consistent with H(2)folate and 10-HCO-H(2)folate being the product and substrate for AICAR transformylase. The labeling of purine C(2) by an oral dose of [6RS]-5-H[(13)C]O-H(4)folate in a human subject is consistent with 10-H[(13)C]O-H(2)folate formation from unnatural isomer, [6R]-5-H[(13)C]O-H(4)folate, and it being a substrate for AICAR transformylase. In vitro exchange reactions of purine C(2) using H(4)folate coenzymes are not duplicated in vivo and is consistent with H(2)folate coenzymes being used in vivo by AICAR transformylase.
20444749 Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-we 2010 Jun OBJECTIVE: To evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate. METHODS: Patients were randomly assigned to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3) and golimumab 100 mg plus methotrexate (group 4). At week 16, patients in groups 1, 2 and 3 who had less than 20% improvement in tender and swollen joints entered early escape. At week 24, patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate. RESULTS: At week 16, 31%, 27% and 17% of patients in groups 1, 2 and 3, respectively, entered early escape. At week 52, 44%, 45%, 64% and 58% of patients in groups 1, 2, 3 and 4, respectively, achieved 20% improvement in the American College of Rheumatology criteria; and 34%, 31%, 42% and 53%, respectively, achieved low disease activity (< or = 3.2) according to the 28-joint disease activity score. Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections. CONCLUSION: The results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks. The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.
20231205 Genetic variations in genes encoding RANK, RANKL, and OPG in rheumatoid arthritis: a case- 2010 May OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor-kappaB (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are thought to play roles in the susceptibility to RA. METHODS: In our case-control study, genomic DNA was obtained from 534 patients with RA who fulfilled the American College of Rheumatology 1987 criteria and 516 healthy control blood donors (HC). We studied 7 single-nucleotide polymorphisms (SNP) in the genes of RANK (2 SNP: rs1805034, rs35211496), OPG (2 SNP: rs3102735, rs2073618), and RANKL (3 SNP: rs9533156, rs2277438, rs1054016) using TaqMan assay-guided polymerase chain reaction. Genotype and allelic frequencies comparing RA patients with HC were analyzed by chi-square test for 2 x 3 and 2 x 2 tables, respectively. RESULTS: Genotype distributions of the SNP rs35211496 in the RANK gene as well as the SNP rs2277438 in the RANKL gene differed significantly between patients with RA and HC. The frequency of the minor allele of rs9533156 of RANKL was significantly higher in patients with RA than in HC (OR 0.84, 95% CI 0.71-0.99, p = 0.047). Multivariate analysis adjusted to sex and investigating SNP demonstrated a significantly elevated risk for RA associated with the major allele in the RANK SNP rs35211496 (p = 0.0231) and with the minor allele in the RANKL SNP rs2277438 (p = 0.0092). No significantly increased risk was detected in the other SNP. CONCLUSION: The minor allele of the RANK SNP rs35211496 may be protective against RA, while the minor alleles of the RANKL SNP rs2277438 may increase susceptibility to RA.
20443365 [The assessment of oral NSAID use in patients with rheumatoid arthritis in Hungary--a cros 2010 Continuous NSAID (nonsteroidal anti-inflammatory drug) therapy is associated with gastrointestinal (GI) and cardiovascular (CV) side effects. In this paper, the oral NSAID use of 143 patients with rheumatoid arthritis was assessed focusing on safety and farmacoeconomic aspects in a cross sectional non interventional study. The most widely used NSAIDs were meloxicam (n = 55, 38.5%) and diclofenac (n = 30, 21%). We found that coxibs were overused (n = 13, 9.1%) compared with the average total coxib consumption in Hungary. According to our results, drugs associated with GI friend side effect profile (meloxicam, celecoxib, etoricoxib) were much preferred in patients with previous GI events, than in patients with low GI risk. The previous occurrence of GI events were significantly higher (p = 0.019) in patients currently treated with safer NSAIDs, probably because of the so-called 'indication bias'. No statistically significant difference in patient's quality of life could be proved between NSAID drug groups. The uses of NSAIDs were considered to be rational concerning CV and GI risk as well as cost-effectiveness.
18818868 Miller-Fisher syndrome in a patient with rheumatoid arthritis treated with adalimumab. 2009 Jan Adalimumab is a frequently prescribed TNFalpha inhibitor for treatment of rheumatoid arthritis. We report on a patient who probably developed a Miller-Fisher syndrome after the second injection of adalimumab.
20391481 Impact of the Medicare Modernization Act of 2003 on utilization and spending for medicare 2010 Mar OBJECTIVE: To examine changes in utilization and expenditures for infliximab in rheumatoid arthritis (RA) patients associated with the 2 changes implemented by the Medicare Prescription Drug Improvement and Modernization Act (MMA) of 2003, specifically 1) reductions in physician reimbursement for Part B drugs between 2003 and 2005 and 2) availability of alternative RA biologics in 2006. METHODS: Using 2002-2006 5% Medicare files, nationally representative estimates of infliximab use and expenditures were estimated in annual cross-sectional samples of RA beneficiaries. Infliximab initiation and continuation rates were estimated in 2-year longitudinal cohorts (2005-2006 versus 2002-2003, 2003-2004, and 2004-2005). RESULTS: Total payments (in 2006 dollars) for infliximab increased from $357 million in 2002 to $492 million in 2006. The largest annual increase in infliximab payments occurred in the pre-MMA period from 2002 to 2003, wherein payments per RA patient increased by 31%. From 2003 to 2004, despite the reduction in payments brought by the MMA, there was a 4% increase in total expenditures for infliximab per RA patient driven by an increase in utilization factors. Total payments for infliximab per RA patient actually decreased from 2004 to 2005, when reimbursement was further reduced. Continuation and initiation rates for infliximab use remained unchanged in 2006, as compared with previous years. CONCLUSION: Infliximab expenditures increased from 2002 to 2006, yet the passage of the MMA was associated with a remarkable slowdown in the rate of increase in expenditures. There was no evidence of significant substitution of infliximab with other biologics made available in 2006.
20205006 Developing a spouse version of the Illness Perception Questionnaire-Revised (IPQ-R) for hu 2009 Apr A husband's beliefs about his wife's rheumatoid arthritis (RA) may be important to his provision of support and well-being. We adapted seven subscales of the Illness Perception Questionnaire-Revised to assess husbands' beliefs about their wives' RA. We recruited 190 couples (average years married = 22; average years with RA = 14) from community settings to complete surveys assessing illness perceptions, psychosocial and illness variables at baseline and four-month follow-up. We conducted exploratory factor analyses, calculated Cronbach's alphas for each factor, and examined construct validity. This process yielded six parallel wife and husband subscales assessing beliefs about the (a) timeline, (b) consequences and (c) cyclical nature of RA, and women's RA (d) emotional responses, (e) control and (f) illness coherence. All items loaded above 0.50 on their respective factors and Cronbach's alphas ranged from 0.72 to 0.86. Subscales were inter-related in a manner consistent with previous research and husbands' beliefs were related to a variety of illness and adjustment variables. The factor structure was replicated in the same sample at follow-up (n = 165). This study introduces an instrument to assess spouse beliefs about RA that may help to elucidate the role of spousal relationships in illness adaptation.
19269955 Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune a 2009 Jun Inflammatory T cells are thought to be central to the pathology of autoimmune arthritis. Th17 cells, CD4 T cells that secrete the pro-inflammatory cytokine IL-17 play a critical role in murine models of arthritis. Recent evidence from human studies suggests that Th17 cells may be important players in several autoimmune diseases, including seronegative arthritis in adults, childhood arthritis [juvenile idiopathic arthritis (JIA)]. It was surprising to find that the development of Th17 cells is closely related to that of an immunoregulatory subset called regulatory T cells (Tregs). Tregs are important in the maintenance of immune homeostasis. Defects in Treg function or reduced numbers have been documented in several human autoimmune diseases, including RA and JIA. Conditions that typically favour the development of Tregs and promote tolerance can be subverted by inflammatory signals towards supporting the generation of Th17 cells. In animal models, the enhancement of Th17 cell differentiation is at the expense of Tregs, and these combined changes trigger autoimmunity. Several mechanisms have come to light that control this reciprocal relationship between Tregs and Th17 cells, including the action of pro-inflammatory cytokines such as IL-1beta. Anti-rheumatic biologic therapies may offer a means of restoring the Th17/Treg balance in favour of Tregs and thereby re-establishing immune tolerance.
19398485 Equivalent osteoblastic differentiation function of human mesenchymal stem cells from rheu 2009 Jun OBJECTIVE: To evaluate the osteoblastic differentiation of human mesenchymal stem cells (hMSCs) in patients with RA. METHODS: Heparinized bone marrow aspirate was obtained from patients with OA and RA. Mononuclear cells were cultured for 2 weeks and a colony-forming assay was performed. The phenotype of cells was analysed by flow cytometry. Passage 2 cells were cultured with beta-glycerophosphate (bGP) in the control group and bGP, ascorbic acid and dexamethasone in the differentiation group. After 2 weeks, ALP staining and activity were performed. After 3 weeks, Alizarin Red S assay was performed. Total RNA was extracted from cells cultured for 2 and 3 weeks. Gene expression of bone formation factor was examined by real-time PCR. RESULTS: The phenotype of cells was identical in both OA and RA and the content was thought to be hMSCs. The results of ALP activity and Alizarin Red S assay showed higher levels in the differentiation group for both OA and RA samples compared with the control group. The results of a colony-forming assay were identical in both OA and RA samples. Gene expression in the differentiation group was higher than in the control group in both OA and RA samples. There was no significant difference between OA and RA samples in all experiments. CONCLUSION: The function of osteoblastic differentiation of hMSCs is similar between OA and RA.
20070408 Expression and regulation of interleukin-33 in human monocytes. 2010 Jun Interleukin-33 (IL-33) is an IL-1 family cytokine that has a role in regulating T helper type 2 cytokines and mast cell development. Expression of IL-33 is also associated with chronic inflammatory conditions such as rheumatoid arthritis. However, there is little information regarding IL-33 in myeloid cell immune responses, which are important in immunity and inflammation. We therefore investigated the expression, intracellular location and regulation of myeloid cell IL-33 by lipopolysaccharide (LPS) from Escherichia coli and the periodontal pathogen Porphyromonas gingivalis. We detected IL-33 messenger RNA in the human promonocytic cell line THP-1, in monocytes derived from these cells and in primary human monocytes. However, IL-33 was not expressed in primary monocyte-derived dendritic cells. Stimulation of monocytes with E. coli LPS (Toll-like receptor 4 agonist) and LPS from P. gingivalis (Toll-like receptor 2 agonist) up-regulated IL-33 at both the messenger RNA and protein levels but IL-1beta and tumour necrosis factor-alpha had no effect. The IL-33 protein was mainly found in the cytoplasm of monocytes with no evidence of nuclear translocation in stimulated cells. Furthermore, no IL-33 secretion was detected after stimulation with LPS and/or ATP. These data indicate that the function, if any, of IL-33 in activated monocytes is primarily intracellular. Interestingly, immunofluorescence analysis indicated that IL-33 was sequestered in the nucleus of monocytes undergoing apoptosis but released into the extracellular milieu by LPS-stimulated cells in which necrosis had been induced by freeze-thawing. Therefore, this endorses the view that IL-33 may function as an 'alarmin' and have a role in signalling cellular damage and inflammatory disease pathogenesis through release from damaged or necrotic cells.
19298527 Survivin is an essential mediator of arthritis interacting with urokinase signalling. 2009 Sep Proto-oncogene survivin has recently been identified as a prognostic marker distinguishing patients with destructive rheumatoid arthritis (RA). In the present material of 132 RA patients and 82 controls, the levels of survivin correlated to urokinase (uPA) (r= 0.46), a plasminogen activator over-expressed in inflamed joints and known to exhibit potent arthritogenic properties. Here we evaluate the functional relationship between these proteins using primary synovial fibroblasts and leucocytes of RA patients, human monocytic (THP-1) and fibroblast (MRC-5) cell lines. Using inhibitors of intracellular signalling, we show that uPA and survivin share common transduction pathways in synovial fibroblasts being dependent on the activity of tyrosine kinases, phosphatidylinositide 3 kinase and mitogen effector kinase. Moreover, uPA production is significantly reduced in fibroblasts if survivin synthesis has been silenced by siRNA. Importantly, silencing of survivin in fibroblasts prevented their invasive growth in knee joints of severe combined immune deficient mice. Interaction of uPA with receptor up-regulates survivin expression in leucocytes. In turn, survivin is required for the up-regulation of uPA receptor on the cell surface. These findings indicate that survivin is an essential mediator of arthritogenic properties of uPA regulating its synthesis in synovial fibroblasts and uPAR expression in leucocytes. Close correlation between survivin and uPA levels in patients with RA supports the importance of this connection for the pathogenesis of arthritis.
19013763 Poor reporting of search strategy and conflict of interest in over 250 narrative and syste 2009 Feb OBJECTIVE: To evaluate the quality of reviews about etanercept (ETN) and infliximab (IFX), two biologic treatments for rheumatoid arthritis (RA). STUDY DESIGN: A comprehensive, systematic review, including searches of MEDLINE, EMBASE, and other electronic databases and hand-searches for published and unpublished literature. Two raters independently examined each article and identified systematic reviews as those including either a description of: (1) sources for identification and data retrieval; or (2) search strategy. They applied the quality of reporting of meta-analyses (QUOROM) instrument to systematic reviews. RESULTS: Of 3,620 total citations, 281 were identified as reviews. Of these, 26 (9%) qualified as systematic rather than narrative. Overall, few reviews described selection of sources, critical appraisal, or quantitative summary or synthesis. Systematic reviews most often failed to explain validity assessment. Several articles did not disclose authors' participation in industry-funded clinical trials. Most reviews published in high impact factor and rheumatology journals did not meet many quality standards. Significant associations existed between review type (narrative vs. systematic) and reported funding (P=0.05), conflicts of interest (P=0.005), and country of publication (P<0.0001). CONCLUSION: More than 90% of the published reviews were narrative and did not report methods and conflicts of interest in sufficient detail, raising concerns about selection and reporting bias.
20504983 Rothia aeria as a cause of sepsis in a native joint. 2010 Jul Rothia aeria is a recently described Gram-positive rod from the family Micrococcaceae. An elderly woman with rheumatoid arthritis and dental abscesses who was undergoing immunosuppression had R. aeria isolated from synovial fluid. This report characterizes this rare organism and contributes to the literature on its pathogenicity and likely oral source.
19922018 Effect of etanercept on serum levels of soluble cell adhesion molecules (sICAM-1, sVCAM-1, 2009 Nov OBJECTIVE: Endothelium and adhesion molecules are engaged in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to analyse the effect of etanercept on the levels of soluble cell adhesion molecules (sCAMs) and vascular endothelial growth factor (VEGF) in patients with active RA. METHODS: Patients were receiving 50 mg/week of subcutaneous etanercept and 10-25 mg/week of methotrexate (MTX). Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and VEGF were measured by enzyme-linked immunosorbent assay (ELISA) in 18 RA patients (prior to injection) at 0, 3, 6, 9, and 12 months. RESULTS: A decrease in serum levels of sICAM-1 (p<0.001), sVCAM-1 (p<0.01), sE-selectin (p<0.01), and VEGF (p<0.001) was observed in RA patients after 3 months of treatment with etanercept. Six months of therapy with etanercept prolonged the suppression of serum sICAM-1 (p<0.01) and even more remarkably diminished sVCAM-1, sE-selectin, and VEGF (in all cases p<0.001) concentrations as compared to baseline (month 0). Treatment also effectively diminished sICAM-1, sVCAM-1, and VEGF levels at months 9 and 12 (in all cases p<0.001), and less significantly sE-selectin (p<0.05 at month 9 and p<0.01 at month 12). The Disease Activity Score including a 28-joint count (DAS28) measured at 3, 6, 9, and 12 months decreased significantly compared to baseline (in all cases p<0.001). CONCLUSION: Our study shows that, besides a rapid suppression of disease activity, serum sCAM and VEGF concentrations are downregulated following anti-tumour necrosis factor alpha (TNFalpha) therapy combined with MTX. Prolonged treatment with etanercept sustained or even more remarkably diminished the sCAM and VEGF serum concentrations.
19404936 The alpha7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovia 2009 May OBJECTIVE: Recent studies have suggested an important role for neurotransmitters as modulators of inflammation. Therefore, we undertook this study to investigate the expression of the alpha7 subunit of the nicotinic acetylcholine receptor (alpha7nAChR) and its function in rheumatoid arthritis (RA). METHODS: The potential role of the alpha7nAChR in modulating proinflammatory cytokine expression in fibroblast-like synoviocytes (FLS) was identified by screening an adenoviral short hairpin RNA (Ad.shRNA) library. An alpha7-specific antibody was used for immunohistochemistry, and fluorescein isothiocyanate-labeled alpha-bungarotoxin, which binds specifically to the alpha7nAChR, was used for immunofluorescence. Gene expression in FLS was determined by quantitative polymerase chain reaction with primers specific for the alpha7nAChR. In addition, we analyzed messenger RNA (mRNA) expression of dupalpha7, a variant alpha7 transcript. Next, we studied the functional role of the alpha7nAChR in RA FLS by examining the effects of alpha7-specific agonists on the production of interleukin-6 (IL-6) and IL-8 by activated FLS. RESULTS: A screen using an Ad.shRNA library against 807 transcripts revealed that a specific alpha7nAChR shRNA potently modulated IL-8 and matrix metalloproteinase expression in FLS. The alpha7nAChR was expressed in the inflamed synovium from RA patients, predominantly in the intimal lining layer. We found alpha7nAChR expression at both the mRNA and protein level in cultured RA FLS. FLS also constitutively expressed dupalpha7 mRNA. Specific alpha7nAChR agonists reduced tumor necrosis factor alpha-induced IL-6 and IL-8 production by FLS. CONCLUSION: The alpha7nAChR and its dupalpha7 variant are expressed in RA synovium, where they may play a critical role in regulating inflammation. Targeting the alpha7nAChR could provide a novel antiinflammatory approach to the treatment of RA.